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Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.
Emdal, Kristina B; Palacio-Escat, Nicolàs; Wigerup, Caroline; Eguchi, Akihiro; Nilsson, Helén; Bekker-Jensen, Dorte B; Rönnstrand, Lars; Kazi, Julhash U; Puissant, Alexandre; Itzykson, Raphaël; Saez-Rodriguez, Julio; Masson, Kristina; Blume-Jensen, Peter; Olsen, Jesper V.
Afiliação
  • Emdal KB; Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Palacio-Escat N; Heidelberg University, Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant-Zentrum, Heidelberg, Germany; Heidelberg University, Faculty of Biosciences, Heidelberg, Germany; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Co
  • Wigerup C; Acrivon Therapeutics Inc., Watertown, MA, USA.
  • Eguchi A; Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Nilsson H; Acrivon Therapeutics Inc., Watertown, MA, USA.
  • Bekker-Jensen DB; Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Rönnstrand L; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Kazi JU; Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
  • Puissant A; INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
  • Itzykson R; INSERM UMR 944, IRSL, St Louis Hospital, Paris, France.
  • Saez-Rodriguez J; Heidelberg University, Faculty of Medicine and Heidelberg University Hospital, Institute for Computational Biomedicine, BioQuant-Zentrum, Heidelberg, Germany; RWTH Aachen University, Faculty of Medicine, Joint Research Centre for Computational Biomedicine, Aachen, Germany. Electronic address: pub.sa
  • Masson K; Acrivon Therapeutics Inc., Watertown, MA, USA. Electronic address: kmasson@acrivon.com.
  • Blume-Jensen P; Acrivon Therapeutics Inc., Watertown, MA, USA. Electronic address: pblumejensen@acrivon.com.
  • Olsen JV; Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: jesper.olsen@cpr.ku.dk.
Cell Rep ; 40(6): 111177, 2022 08 09.
Article em En | MEDLINE | ID: mdl-35947955
ABSTRACT
Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article